The human relevant potency threshold: Reducing uncertainty by human calibration of cumulative risk assessments

Regulatory Toxicology and Pharmacology

Volumn 62, Issue 2, 2012, Pages 313-328

  Borgert, C J ^a,b   Sargent, E V ^c   Casella, G ^b   Dietrich, D R ^d   McCarty, L S ^e   Golden, R J ^f  

^a Applied Pharmacology and Toxicology Inc   (United States)

^b UNIVERSITY OF FLORIDA   (United States)

^c UNIVERSITY OF MEDICINE AND DENTISTRY OF NEW JERSEY   (United States)

^d UNIVERSITY OF KONSTANZ   (Germany)

^e LS McCarty Scientific Research and Consulting   (Canada)

^f ToxLogic LLC   (United States)

Author keywords

Anti androgens; Chemical mixtures; Cumulative risk assessment; Diethylstilbestrol; Dose addition; Endocrine disruptor; Finasteride; Human relevance; Independent action; Phthalate esters

Indexed keywords

4,4' ISOPROPYLIDENEDIPHENOL; ANTIANDROGEN; BUTYL PARABEN; DIISOBUTYLPHTHALATE; FENITROTHION; FINASTERIDE; FLUTAMIDE; LINURON; PHTHALIC ACID BENZYL BUTYL ESTER; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; PHTHALIC ACID DERIVATIVE; PHTHALIC ACID DIBUTYL ESTER; PHTHALIC ACID DIISONONYL ESTER; PHTHALIC ACID DIPENTYL ESTER; POLYBROMINATED DIPHENYL ETHER; PROCHLORAZ; PROCYMIDONE; PROPYL PARABEN; UNCLASSIFIED DRUG; VINCLOZOLIN;

ACCURACY; ADVERSE OUTCOME; ARTICLE; CALIBRATION; CUMULATIVE RISK ASSESSMENT; DATA ANALYSIS; DOSE RESPONSE; HEALTH HAZARD; HUMAN; HUMAN VERSUS ANIMAL COMPARISON; NONHUMAN; OUTCOMES RESEARCH; PREDICTION; PRIORITY JOURNAL; RISK ASSESSMENT; TOXICITY TESTING; UNCERTAINTY;

ANDROGEN ANTAGONISTS; ANIMALS; CALIBRATION; DIETHYLSTILBESTROL; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDPOINT DETERMINATION; FINASTERIDE; HUMANS; RATS; RESEARCH DESIGN; RISK ASSESSMENT; SPECIES SPECIFICITY; UNCERTAINTY;

EID: 84857374218     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2011.10.012     Document Type: Article

References (101)

1. Adachi T., Koh K.B., Tainaka H., Matsuno Y., Ono Y., Sakurai K., et al. Toxicogenomic difference between diethylstilbestrol and 17beta-estradiol in mouse testicular gene expression by neonatal exposure. Molecular Reproduction and Development 2004, 67(1):19-25.
2. Adamsson N.A., Brokken L.J., Paranko J., Toppari J. In vivo and in vitro effects of flutamide and diethylstilbestrol on fetal testicular steroidogenesis in the rat. Reproductive Toxicology 2008, 25(1):76-83.
3. Adeshina, F. and Todd, E.L., 1991. Exposure assessment of chlorinated pesticides in the environment. Journal of Environmental Science and Health: Part A: Environmental Science and Engineering (USA).
4. Andric S.A., Kostic T.S., Dragisic S.M., Andric N.L., Stojilkovic S.S., Kovacevic R.Z. Acute effects of polychlorinated biphenyl-containing and -free transformer fluids on rat testicular steroidogenesis. Environmental Health Perspectives 2000, 108(10):955-959.
5. Andric S.A., Kostic T.S., Stojilkovic S.S., Kovacevic R.Z. Inhibition of rat testicular androgenesis by a polychlorinated biphenyl mixture aroclor 1248. Biology of Reproduction 2000, 62(6):1882-1888.
6. Ashby J. Problems associated with the recognition and confirmation of low-dose endocrine toxicities. Nonlinearity in Biology, Toxicology. Medicine 2003, 1(4):439-453.
7. Ashby J., Lefevre P.A., Tinwell H., Odum J., Owens W. Testosterone-stimulated weanlings as an alternative to castrated male rats in the hershberger anti-androgen assay. Regulatory Toxicology and Pharmacology 2004, 39(2):229-238.
8. ATSDR (Agency for Toxic Substances and Disease Registry), 2001a. Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures. Final/Technical Report. U.S. Department of Health and Human Services, Public Health Service Agency for Toxic Substance and Disease Registry, Atlanta, GA, USA.
9. ATSDR (Agency for Toxic Substances and Disease Registry), 2001b. Guidance for the Preparation of an Interaction Profile.
10. Axmon A., Hagmar L., Jönsson B.A. Rapid decline of persistent organochlorine pollutants in serum among young swedish males. Chemosphere 2008, 70(9):1620-1628.
11. Barton C.N., Braunberg R.C., Friedman L. Nonlinear statistical models for the joint action of toxins. Biometrics 1993, 49:95-105.
12. Bartsch G., Rittmaster R.S., Klocker H. Dihydrotestosterone and the concept of 5α-reductase inhibition in human benign prostatic hyperplasia. European Urology 2002, 37(4):367-380.
13. Benson R. Hazard to the developing male reproductive system from cumulative exposure to phthalate esters-dibutyl phthalate, diisobutyl phthalate, butylbenzyl phthalate, diethylhexyl phthalate, dipentyl phthalate, and diisononyl phthalate. Regulatory Toxicology and Pharmacology 2009, 53(2):90-101.
14. Borgert C.J., Price B., Wells C.S., Simon G.S. Evaluating chemical interaction studies for mixture risk assessment. Human and Ecological Risk Assessment 2001, 7(2):259-306.
15. Borgert C.J., Quill T.F., McCarty L.S., Mason A.M. Can mode of action predict mixtures toxicity for risk assessment?. Toxicology and Applied Pharmacology 2004, 201(2):85-96.
16. Borgert C.J., Borgert S.A., Findley K.C. Synergism, antagonism, or additivity of dietary supplements: application of theory to case studies. Thrombosis Research 2005, 117(1-2):123-132.
17. Bowman C.J., Barlow N.J., Turner K.J., Wallace D.G., Foster P.M.D. Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. Toxicological Sciences 2003, 74(2):393-406.
18. Cassee F.R., Groten J.P., Bladeren P.J., Feron V.J. Toxicological evaluation and risk assessment of chemical mixtures. Critical Reviews in Toxicology 1998, 28(1):73-101.
19. CDC, 2005. Third National Report on Human Exposure to Environmental Chemicals, Atlanta, GA., NCEH Pub. No. 05-0570. July 2005.
20. Christiansen S., Scholze M., Axelstad M., Boberg J., Kortenkamp A., Hass U. Combined exposure to anti-androgens causes markedly increased frequencies of hypospadias in the rat. International Journal of Andrology 2008, 31(2):241-248.
21. Christiansen S., Scholze M., Dalgaard M., Vinggaard A.M., Axelstad M., Kortenkamp A., Hass U. Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. Environmental Health Perspectives 2009, 117(12):1839-1846.
22. Clark R.L., Antonello J.M., Grossman S.J., et al. External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor. Teratology 1990, 42(1):91-100.
23. Cook J.C., Klinefelter G.R., Hardisty J.F., Sharpe R.M., Foster P.M. Rodent leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Critical Reviews in Toxicology 1999, 29(2):169-261.
24. Couse J.F., Korach K.S. Estrogen receptor-alpha mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract. Toxicology 2004, 205(1-2):55-63.
25. David R.M. Proposed mode of action for in utero effects of some phthalate esters on the developing male reproductive tract. Toxicologic Pathology 2006, 34:209-219.
26. Dietrich D.R. Courage for simplification and imperfection in the 21st century assessment of " endocrine disruption" ALTEX 2010, 27(4):264-278.
27. Efron B., Tibshirani R. An Introduction to the Bootstrap 1993, Springer-Verlag, New York.
28. Fernandez M.F., Olmos B., Granada A., López-Espinosa M.J., Molina-Molina J.M., Fernandez J.M., et al. Human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias: a nested case-control study. Environmental Health Perspectives 2007, 115(Suppl. 1):8-14.
29. Filipiak E., Walczak-Jedrzejowska R., Oszukowska E., et al. Xenoestrogens diethylstilbestrol and zearalenone negatively influence pubertal rat's testis. Folia Histochemica Et Cytobiologica, Polish Academy of Sciences. Polish Histochemical and Cytochemical Society 2009, 47(5):S113-S120.
30. Fisch H., Golden R.J., Liberson G.L., Hyun G.S., Madsen P., New M.I., Hensle T.W. Maternal age as a risk factor for hypospadias. Journal of Urology 2001, 165:934-936.
31. Foster P.M. Mode of action: impaired fetal Leydig cell function-effects on male reproductive development produced by certain phthalate esters. Critical Reviews in Toxicology 2005, 35(8-9):713-719.
32. Gaido K.W., Hensley J.B., Liu D., et al. Fetal mouse phthalate exposure shows that Gonocyte multinucleation is not associated with decreased testicular testosterone. Toxicological Sciences 2007, 97:491-503.
33. Golden R.J., Noller K.L., Titus-Ernstoff L., Kaufman R.H., Mittendorf R., Stillman R., Reese E.A. Environmental endocrine modulators and human health: an assessment of the biological evidence. Critical Reviews in Toxicology 1998, 28(2):109-227.
34. Gormley G.J. Chemoprevention strategies for prostate cancer: the role of 5 alpha-reductase inhibitors. Journal of Cellular Biochemistry, Supplement 1992, 16H:113-117.
35. Gormley G.J., Stoner E., Rittmaster R.S., et al. Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers. The Journal of Clinical Endocrinology and Metabolism 1990, 70(4):1136-1141.
36. Goyal H.O., Braden T.D., Mansour M., et al. Diethylstilbestrol-treated adult rats with altered epididymal sperm numbers and sperm motility parameters, but without alterations in sperm production and sperm morphology. Biology of Reproduction 2001, 64(3):927-934.
37. Goyal H.O., Braden T.D., Williams C.S., et al. Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study. Biology of Reproduction 2004, 70(5):1504-1517.
38. Goyal H.O., Braden T.D., Williams C.S., et al. Permanent induction of morphological abnormalities in the penis and penile skeletal muscles in adult rats treated neonatally with diethylstilbestrol or estradiol valerate: a dose-response study. Journal of Andrology 2005, 26(1):32-43.
39. Goyal H.O., Braden T.D., Williams C.S., Williams J.W. Estrogen-Induced developmental disorders of the rat penis involve both estrogen receptor (ESR)- and androgen receptor (AR)-mediated pathways. Biology of Reproduction 2009, 81(3):507-516.
40. Gray L.E., Kelce W.R., Monosson E., Ostby J.S., Birnbaum L.S. Exposure to TCDD during development permanently alters reproductive function in male long evans rats and hamsters: reduced ejaculated and epididymal sperm numbers and sex accessory gland weights in offspring with normal androgenic status. Toxicology and Applied Pharmacology 1995, 131(1):108-118.
41. Gray L.E., Ostby J.S., Kelce W.R. A dose-response analysis of the reproductive effects of a single gestational dose of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin in male long evans hooded rat offspring. Toxicology and Applied Pharmacology 1997, 146(1):11-20.
42. Gray L.E., Wolf C., Lambright C., et al. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. Toxicology and Industrial Health 1999, 15(1-2):94-118.
43. Guyot R., Odet F., Leduque P., Forest M.G., Le Magueresse-Battistoni B. Diethylstilbestrol inhibits the expression of the steroidogenic acute regulatory protein in mouse fetal testis. Molecular and Cellular Endocrinology 2004, 220(1-2):67-75.
44. Haavisto T., Nurmela K., Pohjanvirta R., et al. Prenatal testosterone and luteinizing hormone levels in male rats exposed during pregnancy to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin and diethylstilbestrol. Molecular and Cellular Endocrinology 2001, 178(1-2):169-179.
45. Haavisto T.E., Adamsson N.A., Myllymaki S.A., et al. Effects of 4-tert-octylphenol, 4-tert-butylphenol, and diethylstilbestrol on prenatal testosterone surge in the rat. Reproductive Toxicology 2003, 17(5):593-605.
46. Hallmark N., Walker M., McKinnell C., et al. Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environmental Health Perspectives 2007, 115:390-396.
47. Haschek W.M., Rousseaux C.G., Wallig M.A. (eds.), 2010. Nomenclature: terminology for Morphological Alterations, Chapter 4. Fundamentals of Toxicologic Pathology, 2nd ed. London.
48. Hass U., Scholze M., Christiansen S., et al. Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. Environmental Health Perspectives 2007, 115(Suppl. 1):122-128.
49. Hays S.M., Aylward L.L. Temporal trends in body-burden suggest that dioxin exposure in the general population have declined significantly. Organohalogen Compounds 2001, 52:214.
50. Hogan M.D., Newbold R.R., McLachlan J.A. Extrapolation of teratogenic responses observed in laboratory animals to humans: DES as an illustrative example. Developmental Toxicology: Mechanisms and Risks, Banbury Report 26 1987, 257-269. Cold Spring Harbor Laboratory, Cold Spring Harbor. J.A. McLachlan, R.M. Pratt, C.L. Markert (Eds.).
51. Hotchkiss A.K., Parks-Saldutti L.G., Ostby J.S., et al. A mixture of the " antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biology of Reproduction 2004, 71(6):1852-1861.
52. Hovinga M.E., Sowers M., Humphrey H.E.B. Historical changes in serum PCB and DDT levels in an environmentally-exposed cohort. Archives of Environmental Contamination and Toxicology 1992, 22(4):362-366.
53. Howdeshell K.L., Furr J., Lambright C.R., et al. Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. Toxicological Sciences 2007, 99(1):190-202.
54. Howdeshell K.L., Rider C.V., Wilson V.S., et al. Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats. Environmental Research 2008, 108(2):168-176.
55. Howdeshell K.L., Wilson V.S., Furr J., et al. A mixture of five phthalate esters inhibits fetal testicular testosterone production in the Sprague-Dawley rat in a cumulative, dose-additive manner. Toxicological Sciences 2008, 105(1):153-165.
56. Ikeda Y., Tanaka H., Esaki M. Effects of gestational diethylstilbestrol treatment on male and female gonads during early embryonic development. Endocrinology 2008, 149(8):3970-3979.
57. Johnson K.J., McDowell E.N., Viereck M.P., et al. Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression pathways. Toxicological Sciences 2011, 120(2):460-474.
58. Kelce W.R., Stone C.R., Laws S.C., Gray L.E., Kemppainen J.A., Wilson E.M. Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist. Nature 1995, 375(6532):581-585.
59. Kennel P.F., Pallen C.T., Bars R.G. Evaluation of the rodent hershberger assay using three reference endocrine disrupters (androgen and antiandrogens). Reproductive Toxicology 2004, 18(1):63-73.
60. Khan S.A., Ball R.B., Hendry W.J. Effects of neonatal administration of diethylstilbestrol in male hamsters: disruption of reproductive function in adults after apparently normal pubertal development. Biology of Reproduction 1998, 58(1):137-142.
61. Klinger M.M., MacCarter G.D., Boozer C.N. Body weight and composition in the sprague dawley rat: Comparison of three outbred sources. Laboratory Animal Science 1996, 46(1):67-70.
62. Kortenkamp A., Faust M. Combined exposures to anti-androgenic chemicals: Steps towards cumulative risk assessment. International Journal of Andrology 2010, 33(2):463-474.
63. Krishnan K., Brodeur J. Toxic interactions among environmental pollutants: Corroborating laboratory observations with human experience. Environmental Health Perspectives 1994, 102(Suppl. 9):11-17.
64. Kristensen D.M., Hass U., Lesné L., Lottrup G., Jacobsen P.R., Desdoits-Lethimonier C., et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Human Reproduction (Oxford, England) 2011, 26(1):235-244.
65. Lambrot R., Muczynski V., Lécureuil C., et al. Phthalates impair germ cell development in the human fetal testis in vitro without change in testosterone production. Environmental Health Perspectives 2009, 117(1):32-37.
66. Laska E.M., Meisner M., Siegel C. Simple designs and model-free tests for synergy. Biometrics 1994, 50:834-841.
67. Lassurguere J., Livera G., Habert R., et al. Time- and dose-related effects of estradiol and diethylstilbestrol on the morphology and function of the fetal rat testis in culture. Toxicological Sciences 2003, 73(1):160-169.
68. Leary F.J., Resseguie L.J., Kurland L.T., O'Brien P.C., Emslander R.F., Noller K.L. Males exposed in utero to diethylstilbestrol. J. Amer. Med. Assoc. 1984, 252:2984.
69. Marty M.S., Crissman J.W., Carney E.W. Evaluation of the male pubertal onset assay to detect testosterone and steroid biosynthesis inhibitors in CD rats. Toxicological Sciences 2001, 60(2):285-295.
70. Mathews E., Braden T.D., Williams C.S., et al. Mal-Development of the penis and loss of fertility in male rats treated neonatally with female contraceptive 17alpha-ethinyl estradiol: a dose-response study and a comparative study with a known estrogenic teratogen diethylstilbestrol. Toxicological Sciences 2009, 112(2):331-343.
71. McConnell J.D. The role of dihydrotestosterone in benign prostatic hyperplasia. Current Opinion in Urology 1992, 2(1):18.
72. McKinnell C., Atanassova N., Williams K., et al. Suppression of androgen action and the induction of gross abnormalities of the reproductive tract in male rats treated neonatally with diethylstilbestrol. Journal of Andrology 2001, 22(2):323-338.
73. Metzdorff S.B., Dalgaard M., Christiansen S., et al. Dysgenesis and histological changes of genitals and perturbations of gene expression in male rats after in utero exposure to antiandrogen mixtures. Toxicological Sciences 2007, 98(1):87-98.
74. Mikkilä T.F., Toppari J., Paranko J. Effects of neonatal exposure to 4-tert- octylphenol, diethylstilbestrol, and flutamide on steroidogenesis in infantile rat testis. Toxicological Sciences 2006, 91(2):456-466.
75. Mileson B.E., Chambers J.E., Chen W.L., Dettbarn W., Ehrich M., Eldefrawi A.T., et al. Common mechanism of toxicity: A case study of organophosphorus pesticides. Toxicological Sciences: An Official Journal of the Society of Toxicology 1998, 41(1):8-20.
76. Phthalates and Cumulative Risk Assessment: The Task Ahead 2008, NRC (National Research Council), The National Acadamies Press, Washington, DC.
77. Owens W., Gray L.E., Zeiger E., et al. The OECD program to validate the rat hershberger bioassay to screen compounds for in vivo androgen and antiandrogen responses: phase 2 dose-response studies. Environmental Health Perspectives 2007, 115(5):671-678.
78. Petreas M., She J., Visita P., Winkler J., McKinney M., Brown F.R., Dhaliwal J., Denison G., Mok M., 2001. Trends in persistent contaminants in California biota, Symposia Papers Presented Before the Division of Environmental Chemistry, American Chemical Society, San Diego, CA, April 1-5, 2001.
79. Price B., Borgert C.J., Wells C.S., Simon G.S. Assessing toxicity of mixtures: the search for economical study designs. Human and Ecological Risk Assessment: An International Journal 2002, 8(2):305-326.
80. Pullen A.H. A parametric analysis of the growing CFHB (wistar) rat. Journal of Anatomy 1976, 121(Pt 2):371-383.
81. Rider C.V., Furr J., Wilson V.S., et al. A mixture of seven antiandrogens induces reproductive malformations in rats. International Journal of Andrology 2008, 31(2):249-262.
82. Rider C.V., Wilson V.S., Howdeshell K.L., et al. Cumulative effects of in utero administration of mixtures of " antiandrogens" on male rat reproductive development. Toxicologic Pathology 2009, 37(1):100-113.
83. Rivas A., McKinnell C., Fisher J.S., Atanassova N., Williams K., Sharpe R.M. Neonatal coadministration of testosterone with diethylstilbestrol prevents diethylstilbestrol induction of most reproductive tract abnormalities in male rats. Journal of Andrology 2003, 24(4):557-567.
84. Safe S.H. Polychlorinated biphenyls (pcbs), dibenzo-p-dioxins (pcdds), dibenzofurans (pcdfs), and related compounds: environmental and mechanistic considerations which support the development of toxic equivalency factors (tefs). Critical Reviews in Toxicology 1990, 21(1):51-88.
85. Safe S.H. Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. Environmental Health Perspectives 1998, 106(Suppl. 4):1051-1058.
86. Scott H.M., Mason J.I., Sharpe R.M. Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocrine Reviews 2009, 30(7):883-925.
87. Sharpe R.M. The 'oestrogen hypothesis'- where do we stand now?. International Journal of Andrology 2003, 26(1):2-15.
88. Skakkebaek N.E., Rajpert-De Meyts E., Main K.M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: Opinion. Human Reproduction 2001, 16(5):972.
89. Slikker W., Andersen M.E., Bogdanffy M.S., Bus J.S., Cohen S.D., Conolly R.B., et al. Dose-Dependent transitions in mechanisms of toxicity. Toxicology and Applied Pharmacology 2004, 201(3):203-225.
90. Steiner J.F. Clinical pharmacokinetics and pharmacodynamics of finasteride. Clinical pharmacokinetics 1996, 30(1):16-27.
91. Tallarida R.J. An overview of drug combination analysis with isobolograms. The Journal of Pharmacology and Experimental Therapeutics 2006, 319(1):1-7.
92. Tallarida R.J. Interactions between drugs and occupied receptors. Pharmacology & Therapeutics 2007, 113(1):197-209.
93. Thorup J., McLachlan R., Cortes D., Nation T.R., Balic A., Southwell B.R., et al. What is new in cryptorchidism and hypospadias-a critical review on the testicular dysgenesis hypothesis. Journal of Pediatric Surgery 2010, 45(10):2074-2086.
94. Toppari J., Virtanen H.E., Main K.M., Skakkebaek N.E. Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Research. Part A. Clinical and Molecular Teratology 2010, 88(10):910-919.
95. USDHHS (U.S. Department of Health and Human Services, Public Health Service Agency for Toxic Substance and Disease Registry), 2001. Guidance Manual for the Assessment of Joint Toxic Action of Chemical Mixtures. Final/Technical Report. Atlanta, GA, USA.
96. Guidelines for the Health Risk Assessment of Chemical Mixtures U.S 1986, USEPA (United States Environmental Protection Agency), Environmental Protection Agency, Washington, DC.
97. Office of Emergency and Remedial Response. Risk assessment guidance for Superfund. Volume 1 Human health evaluation manual (Part A) 1989, USEPA (United States Environmental Protection Agency), Interim final U.S. Environmental Protection Agency, Washington, DC.
98. Guidance for Identifying Pesticide Chemicals That Have a Common Mechanism of Toxicity U.S 1999, USEPA (United States Environmental Protection Agency), Environmental Protection Agency, Washington, DC.
99. Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures U.S 2000, USEPA (United States Environmental Protection Agency), Environmental Protection Agency, Washington, DC.
100. USEPA, 2006. An inventory of sources and environmental releases of dioxin-like compounds in the United States for the years 1987, 1995, and 2000. National Center for Environmental Assessment, Washington, DC, EPA/600/P-03/002F.
101. Warita K., Mitsuhashi T., Sugawara T., Tabuchi Y., Tanida T., Wang Z.Y., et al. Direct effects of diethylstilbestrol on the gene expression of the cholesterol side-chain cleavage enzyme (p450scc) in testicular leydig cells. Life Sciences 2010, 87(9-10):281-285.